PROJECT SUMMARY ABSTRACT The overarching goals of this R01 proposal are to improve scientific understanding of potential mechanisms by which ophthalmic diseases lead to the risk of Alzheimer’s disease. The investigators will leverage modern ophthalmic data with state-of-the-art imaging and extensive archived clinical data from a well-characterized cohort of older adults. The investigators propose to examine the effect of structural and functional changes in retina and longitudinal severity of ophthalmic diseases on Alzheimer’s disease and related neuropathology. The proposal builds on the resources of the Adult Changes in Thought (ACT) study, a prospective longitudinal, population-based, dementia-free cohort of over 5,500 people to date established in 1994 which has detected >1,014 research quality diagnoses of Alzheimer’s disease and >1,254 dementia to date. ACT follows consenting participants to autopsy and has performed state-of-the arts autopsy on >781 decedents to date. In this extremely well-characterized cohort, the investigators found that several ophthalmic diseases (diabetic retinopathy, glaucoma, age-related macular degeneration) are significantly associated with the risk of developing Alzheimer’s disease. The investigators will use three advanced ophthalmic imaging modalities at both home and clinical research study visits: fundus photography, optical coherence tomography (OCT), and OCT angiography (OCTA), to obtain quantitative data relevant to these ophthalmic diseases. The study team will establish the distribution (Aim 1a) and 2- and 4-year evolution of ophthalmic imaging characteristics found in older adults in the community and determine associations with change in cognition (Aim 1 b, c). Additionally, magnetic resonance imaging (MRI) and MRI angiography (MRA) will be obtained in a subset of participants to investigate the contribution of small (retinal) and large (cerebral) vascular disease towards cognitive changes (Aim 1d). The study team will continue ACT study’s strong commitment for meaningful data sharing. In collaboration with the Laboratory of Neuro Imaging at University of Southern California, the study team will promulgate these ophthalmic data in addition to neuroimaging data to the research community (Aim 1e). In Aim 2, the investigators will use extensive clinical ophthalmology data captured over many decades and incorporate them in novel longitudinal models of eye disease severity. The investigators will analyze eye disease severity along with extensive neuropathology data from the ACT study, including both standard (Aim 2a) and novel quantitative (Aim 2b) neuropathology data, to further scientific understanding of neuropathological mechanisms underlying associations between eye conditions and Alzheimer’s disease risk. The brain is not amenable to direct observations during life. In contrast, the eye is an anterior extension of the central nervous system and may provide a valuable window to illuminate neurodegenerative processes in the aging brain. Proposed investigations will substantially enhance scientific understanding of the role of modern ophthalmic evaluations in delineating risk of Alzheimer's disease and other forms of neuropathology.

PROJECT NARRATIVE Using a large, well-characterized, longitudinal, prospective, cohort study, the study team previously found that diabetic retinopathy, glaucoma, and age-related macular degeneration were significantly associated with Alzheimer’s disease risk. The team proposes to use three cutting edge ophthalmic imaging modalities to obtain quantitative data at both home and clinic research study visits in addition to MRI and MRA in a subset of participants to evaluate their associations with change in cognition over time (Aim 1). The team will leverage extensive ophthalmic clinical and neuropathological data already available for 781 study participants to date as well as new state-of-the-art quantitative measures of beta amyloid (A1-42) and phosphorylated tau to elucidate mechanisms underlying associations between ophthalmic conditions and Alzheimer’s disease (Aim 2).